Therapies to reduce the mortality of sepsis still need to be developed due to the high morbidity and mortality of the disease. We have strong preliminary data indicating that local tissue hypoxia coupled with an increase in extracellular adenosine suppresses the ability of cells to eradicate bacteria. Failure to appropriately control bacteria results in excessive and prolonged inflammation. This proposal will evaluate 2 different modalities to treat sepsis by 1) blocking specific adenosine receptors and 2) providing supplemental oxygen. To increase the applicability of the findings, 4 different murine sepsis models will be studied. The first model is the acute phase of sepsis present in the first four days after cecal ligation and puncture (CLP) and the second model is the chronic phase of sepsis where deaths occur after day five. The third sepsis model evaluates the treatment modalities in a model of trauma (abdominal incision) plus Pseudomonas pneumonia. The fourth will use the recently developed humanized mouse model of sepsis induced by CLP. Our first specific aim will closely study the role of adenosine in sepsis by treating septic mice with specific A2A and A2B receptor antagonists. We will confirm the specificity of these findings using A2A and A2B receptor knockout mice. A novel approach of using biomarkers to direct blockade of the adenosine receptors will also be employed. The second aim will verify that local hypoxia occurs during sepsis and provide supplemental oxygen to improve outcome. The third aim will combine adenosine receptor blockade with supplemental oxygen to determine the potential synergistic interactions of the treatments. The fourth specific aim will closely examine the cellular mechanisms of how these treatment strategies improve outcome by determining the augmented pathways that result in improved bacterial clearance. If successful, this application offers both new treatment strategies for sepsis, and the mechanistic knowledge to understand why they are effective.